NAD+ for Longevity, Long-term Cognition, and Energy

Niacin appears to promote insulin resistance in most, if not all, subjects who take more than a gram daily for weeks at a time. This insulin resistance is initially associated with an increase in fasting glucose due to decreased disposal rates (the speed at which glucose is moved from the blood to tissues), with later increases in fasting insulin levels.

 

NMN has, anecdotally, treated allergies, sinus infections, and arthritis as shown in this video.

 

NAD boosters such as nicotinamide riboside can prevent amyloid accumulation in worms and mice that are models of Alzheimer’s disease.

 

Nicotinamide riboside, a naturally occurring dietary supplement, can enter the brain and alter the metabolism of relevant biological pathways involved in neurodegenerative diseases like Alzheimer’s. But, according to this video, brain levels of NAD+ change very little due to oral dosing of NR or NMN. Perhaps the best way to increase NAD+ in the brain is via exercise, as Dr. Brad Stanfield says.

 

Oral NR supplementation (500 mg, 2x /day, 6 weeks) increases NAD⁺ levels in the brain of 22 healthy older adults. Orally administered NR can augment neuronal NAD⁺ levels and modify biomarkers related to neurodegenerative pathology in humans.

 

NAD+ declines during ageing due to increased  CD38 enzyme activity. Dr. Brad Stanfield says, in this video, that older adults who exercise have NAD+ levels similar to those who are younger. Also, NAD+ levels are raised by a similar amount with niacin compared with NMN or NR.

 

NMN may be best taken in the morning. This study of 30 healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks showed that oral administration of NMN is a safe and practical strategy to boost NAD⁺ levels in humans. The NAD+ salvage pathway is dependent on SIRT1.  NAMPT and NAD⁺ levels oscillate during the daily 24-hour cycle and that this oscillation is regulated by the circadian clock. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels.

 

This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial included 80 middle-aged healthy adults being randomized for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. NMN supplementation was well tolerated. Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60, with longest walking distances measured in the 600 mg and 900 mg groups. The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo.

 

Oxidative stress

Oxidative stress and decreased DNA damage repair in vertebrates increase with age also due to lowered cellular NAD+. NAD+ depletion may play a major role in the aging process at the cellular level by limiting (1) energy production, (2) DNA repair, and (3) genomic signaling.

 

NAD+ plays a pivotal role in the regulation of DNA repair, stress resistance, and cell death.

 

Aging at the cellular level is associated with a decline of NAD+ and that NAD+ restoration can reverse phenotypes of aging by inducing cellular repair and stress resistance. Adequate intracellular NAD+ concentrations may be an important longevity assurance factor, while lowered cellular NAD+ concentration may negatively influence the life span.

 

Exogenous NAD⁺ administration suppresses H₂O₂-induced oxidative stress and protects retinal pigment epithelium cells against PARP-1 mediated necrotic death through the up-regulation of autophagy. The results suggest that exogenous NAD⁺ administration might be potential value for the treatment of age-related macular degeneration.

 

The strong positive correlation observed in rats between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.

 

This study of human skin cells showed that NAD⁺ depletion may play a major role in the aging process, by limiting energy production, DNA repair and genomic signalling.

 

NMN supplementation leads to significant increase in intracellular NAD⁺ level, NAD⁺/ NADH ratio, Sirt3 expression, as well as ameliorated mitochondrial function and rescued senescent mesenchymal stem cells (MSCs). Additionally, Sirt3 over-expression relieved mitochondrial dysfunction, and retrieved senescence-associated phenotypic features in MSCs.

Across the kingdom of life, an increase in intracellular levels of NAD+ triggers shifts that enhance survival, including boosting energy production and upregulating cellular repair.⁵ In fact, the slow, ineluctable process of aging has been described as a “cascade of robustness breakdown triggered by a decrease in systemic NAD+ biosynthesis and the resultant functional defects in susceptible organs and tissues.”⁶ By middle age, our NAD+ levels have plummeted to half that of our youth.⁹ Numerous studies have demonstrated that boosting NAD+ levels increases insulin sensitivity, reverses mitochondrial dysfunction, and extends lifespan.^10,11

 

Reduced stem cell function leads to the diminished replenishment of the tissue in essentially all adult stem cell compartments.^108,109,110 The lack of efficient repair of these damaged tissues is the consequence of stem cell decline and aging.^111,112 The importance of NAD⁺ for maintaining the pool and pluripotency of stem cells makes it an essential cofactor during aging.

 

NAD+ level can be regulated by lifestyle and nutrition approaches such as fasting, caloric restriction, sports activity (exercise), low glucose availability (ketosis or calorie restriction), and heat shocks. NAD+ is reduced with age at a cellular, tissue, and organismal level due to inflammation. Strategies that conserve cellular NAD(+) may reprogram dysfunctional adult stem cells and improve life span in mammals. NAD+ level can take 4-6 weeks to stabilize.

 

In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting. NAMPT decreases with age in human skeletal muscle. Aerobic exercise training increased NAMPT abundance 12% and 28% in young and older (≥55 years) individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively.

 

NAD + salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity.

 

This study of 16 untrained participants, 59±4 years old, completed 10 weeks of full-body resistance training (2 d/wk) showed that muscle NAD+, NADH, and global SIRT activity are positively affected by resistance training in middle-aged, untrained individuals to the level of college-age participants.

 

250 mg NMN per day to 65 aged men aged 65+ for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. Significant improvement in gait speed and the 30-second chair stand test were observed. This study showed that chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

 

300 mg was given to post-menopausal women (mean age 55.0 years) . HbA1c in glucose metabolism decreased from 5.34to 5.23 % and HDL-C in lipid metabolism increased from 67.5 to 72.3 mg/dL. T cells increased and skin quality improved.

 

This Healthline piece suggests that “Research in humans has shown that doses of up to 1,200 mg daily are safe to consume.”

 

NMN is found in broccoli, cabbage, cucumber, edamame, tomato, and avocado.

 

Both Dr. Brad Stanfield and Dr.Rhonda Patrick point out that a possible cancer promotion effect of NR and NMN is dependent on senescent cells. This makes a prior period of autophagy a must if one is to use NR or NMN. The FDA banned NMN, possibly because of this study hinting a cancer promotion. That study, however, has been scathingly criticized by Dr. Brad Stanfield. Here is a video suggesting other reasons for banning NMN.

 

In preclinical models of ageing, nutritional insults (high fat–high sucrose diet, alcohol) and various metabolic disorders such as obesity, type 2 diabetes or fatty liver disease, NAD is often severely depleted to levels that impair redox metabolism and reduce the activity of sirtuins.

 

The ratio of NAD⁺/NADH indicates the cellular redox state. A decrease in this ratio affects the cellular anaerobic glycolysis and oxidative phosphorylation functions, which reduces the ability of cells to produce ATP. Therefore, increasing the exogenous NAD⁺ supply under certain disease conditions or in elderly people may be beneficial.

 

NAD+ levels decline with age. ProHealth Longevity’s Uthever NMN one-kilo or 100 gram powder packs are a good bet on purity. ProHealth NMN is sold on AliExpress at a good price.

 

NAD supplementation improves DNA repair, mitochondrial dysfunction & hearing loss in mice.

 

NMN

Most of the NMN studies have been done in mice, often using doses that are excessive by human standards.

 

• In mice, both a high-fat diet and aging compromise NAMPT-mediated NAD biosynthesis, contributing to the pathogenesis of diet- and age-induced type 2 diabetes. 
• Insulin sensitivity has beenincreased via NMN. NMN has been shown to be anti-inflammatory in mice.
• Long-term NMN administration affects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.
• NMN reduces metabolic impairment in male Mouse offspring from obese mothers.
• NMN appears to be stable in water; in one study 93%–99% of NMN was maintained intact in drinking water at room temperature for 7–10 days. NMN also appears to be rapidly absorbed.
• NMN supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.
• NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in mouse skeletal muscle.
• Treating mice with a NAD+ precursor, or “booster,” called NMN improved their cells’ ability to repair DNA damage caused by radiation exposure or old age. “The cells of the old mice were indistinguishable from the young mice, after just one week of treatment” said lead author Professor David Sinclair.
• Feeding mice an NAD+ precursor such as NMN, the telomeres were stabilized. Furthermore, feeding NAD+ precursor to the mice not only maintained telomere length but also improved liver condition in these mice,” Sahin said.
• Longer telomeres were observed in both the mice and volunteers with NMN supplementation, suggesting the potential of NMN use at a pre-aging phase to retard the proceeding of aging.
• NMN reverses age-associated decline in exercise capacity by increasing skeletal muscle capillary density in a Sirt1-dependent manner: After two months of NMN feeding, there was a robust improvement in exercise capacity of old mice, where NMN-fed old mice ran two times greater distance compared to other old mice in a treadmill test.
• Treatment of mice with the NAD+ precursor nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. Interestingly, the NMN treatment did not improve blood vessel density and exercise capacity in young sedentary mice. However, it did boost blood vessel formation and exercise capacity in young mice that had been exercising regularly for a month.
• NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body’s ability to make NMN and, by extension, NAD.”
• A single dose of NMN, administered to male mice, increased hippocampal mitochondria NAD+ pools for up to 24 hr post-treatment. This reduced hippocampal reactive oxygen species levels via SIRT3-driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented. Manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation.
• NMN rejuvenates bone stem cells in mice.
• Of 590 genes differentially expressed in aged mice, 204 of which were restored toward youthful expression levels by NMN treatment. Neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways.
• The decline of NAD+ levels in the heart is accompanied by aging, causing cardiac pathological remodeling and dysfunction. NMN has emerged as a precursor to alleviate age-related cardiac pathophysiological changes by improving cardiac NAD+ homeostasis.
• NMN prevents age-associated gene expression changes in a tissue-specific manner.
• Long-term NMN administration significantly improves eye function, bone density, and myeloid-lymphoid composition in aged mice.
• This study from a Japanese University which showed that NMN, either injected or oral, enhanced the effectiveness of Natural Killer (NK) cells in their ability to kill cancer cells in mice.
• In a mouse Alzheimer model, NMN reduced beta-amyloid accumulation.
• NMN has been reported to rapidly increase the level of NAD+ in the hippocampus, hypothalamus, and other brain regions, which further suggests that NMN can pass through the blood-brain barrier, thereby contributing to the biosynthesis of NAD+ in the brain.
• A single dose of NMN, administered to male mice, increased hippocampal mitochondria NAD+ pools for up to 24 hr post-treatment. This reduced hippocampal reactive oxygen species levels via SIRT3-driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented. Manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation.
• Supplementation of NAD+ and its intermediates through diet has also showed promising results in the protection against systemic decline of tissue form and function, as evidenced by the increased resistance to age-related pathogenesis and promotion of healthy aging in mice. Pioneering studies have demonstrated that NMN treatment ameliorates glucose intolerance and insulin insensitivity in diet-induced diabetic mice. NMN treatment of aged mice can bring about rejuvenation of brain function; in particular, it has been shown to improve spatial working memory function and gait coordination, which could be attributed to sirtuin-mediated neurovascular transcriptomic changes.
• NMN treatment blocked UVB-induced photodamage in mice, maintaining normal structure and amount of collagen fibers, normal thickness of epidermis and dermis, reducing the production of mast cells, and maintaining complete organized skin structure. Furthermore, NMN reduced oxidative stress of skin and liver by promoting the activation of the AMP-activated protein kinase (AMPK) signaling pathway and further increasing the expression of downstream antioxidant genes of AMPK.
• NMN mitigated silicosis-induced lung damage in mice at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1, Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2).

 

Trimethylglycine (TMG) is a useful supplement to take if one uses NMN or niacin. Dr. Brad Stanfield explains here.

 

Aerobic and resistance exercise training reverses age‐dependent decline in NAD+ salvage capacity in human skeletal muscle. Aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. Dr. Rhonda Patrick discusses the role of NAD+ recycling and NAMPT here.

 

This 2018 Cell Metabolism paper claims that oral NMN and NR are metabolized in the mouse liver. Unlike in cell culture, where NR and NMN are readily incorporated into NAD, oral administration fails to deliver NR or NMN to tissues without breaking the
nicotinamide-ribose bond. This would render NMN and NR ineffective as oral supplements ???

 

In contrast to the above, this randomized, double-blind placebo-controlled study of humans taking 250 mg NMN in the afternoon appears to significantly improve sleep, reduced drowsiness, and improve some performance of physical tasks. These types of improvements may also impact a person’s day-to-day attitude, which may then improve one’s quality of life and may extend the number of years that they live in overall good health.

 

250 mg NMN per day was given to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

 

This placebo-controlled, randomized, double blind, parallel-group trial showed that giving 250 mg NMN per day to aged men for 6 or 12 weeks (n=21 for 6 weeks, n=10 for 12 weeks) significantly increased the concentrations of NAD+ and NAD+ metabolites. Moreover, NMN significantly improved muscle strength and performance, which were evaluated using the 30-second chair stand test, walking speed, and grip strength, and it showed no significant effect on body composition.

 

In this study of 25 pre-diabetic women, 250 mg of NMN improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice.

 

This study of 80 healthy middle-aged and older adults (40 – 65 years old), both males and females found that blood intracellular NAD levels were found significantly increased in response to 300 mg, 600 mg, and 900 mg NMN oral administration. The study concluded 600 mg daily oral intake is the optimal dose on observation that 900 mg did not give further significant improvement over 600 mg in blood cellular NAD concentration. HOMA-IR values (for insulin sensitivity) were unaffected by NAD+ blood level. There were problems with this study, as pointed out by Dr. Brad Steinfield, though not with the dose vs. blood NAD+ level data.

 

In this study, healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks. No obvious adverse effects were observed. NAD⁺ levels in whole blood were significantly increased after NMN administration. Dr. Brad Steinfield discusses this study in this video.

 

High doses of NAM (nicotinamide) can cause genomic instability, reduce cellular methyl pools, and cause insulin resistance through methylated NAM. NMN overdose may also cause axon degeneration. Tolerance of doses near 1 g (or up to 3 g) of daily intake of NAM, even during long-term administration, has been demonstrated in many studies. There are lots more dreadful effects of high-dose NAM here.

 

Neural stem/progenitor cells (NSPCs) undergo cell divisions to differentiate into the major cell types of the brain, such as neurons, oligodendrocytes, and astrocytes. Aging is a negative regulator of NSPC proliferation, whereas NSPCs could be reactivated in the aged brain: restoring the function of NSPCs could effectively prevent age-associated cognitive decline. NAMPT-mediated NAD+ biosynthesis was critical for NSPC self-renewal, proliferation, and differentiation into oligodendrocytes. Long-term NMN administration was able to maintain the NSPC pool. NMN administration reduced defects in oligodendrogenesis caused by decrease in NAD+ levels. Thus, NMN could be a promising agent for maintaining the NSPC pool and reactivating NSPCs. NMN was able to induce NSC proliferation (via SIRT1 and SIRT2) and promote NSC differentiation (via SIRT1, SIRT2, and SIRT6).

 

This 2019 paper says “dietary NR supplementation has no significant impact on skeletal muscle mitochondria in obese and insulin-resistant men”.

 

Compared to NR, NMN is already one step further down the pathway to produce NAD+: NR => NMN => NAD+. NMN is better than NR.

 

NR is very unstable in the bloodstream: it is quickly degraded into vitamin B3. In contrast, NMN is very stable.

 

Hepatic nutrient-sensing mTOR, AMPK or AKT signaling, became rhythmic specifically in obese mice treated with NAD+ raising therapy just before the active phase. Remarkably, NAD⁺ at the onset of the rest phase was accompanied by uncoupled oscillations between the SCN and the hepatic clock, which were phase inverted in the liver, while keeping behavioral rhythms largely intact. These findings demonstrate that the time of day determines the beneficial effects of NAD⁺-based therapies